The hygiene hypothesis suggests that parasitic infection modulates host immune responses and decreases atopy, but other data suggest parasitic infections may induce allergic responsiveness. To examine the molecular, structural, and immunologic relationships parasite-encoded antigens and manor aeroallergen homologues, parasite- and allergen-specific IgE, IgG, and IgG in sera of filaria-infected and filarial-uninfected atopic individuals were compared using 2 different distinct sets of antigens (tropomyosins or glutathione-S-transferases (GSTs)). For both sets of antigens there was a high degree of identity at the amino acid level, and overlapping predicted 3-dimensional structures. Basophils sensitized with sera from individuals allergic to tropomyosin or GST released histamine similarly when triggered their parasite homologue and animals (non-human primates or mice) infected experimentally with particular helminths induced IgE antibodies that cross-reacted immunologically and functionally with the aeroallergen homologue. To examine systematically the structural relationships among allergens and proteins of pathogens (helminths, protozoans, fungi and bacteria) as they relate to allergenicity, we compared the amino acid sequence of 499 molecularly-defined allergens with the predicted proteomes of fifteen known pathogens, including Th2 inducing helminths and Th1-inducing protozoans, and humans. Allergenicity was assessed based on IgE prevalences using publicly accessible databases. We found multiple homologues of common allergens among proteins of helminths, protozoans, fungi and humans, but not of bacteria. Allergens without homologues or those with limited levels of sequence conservation were the most allergenic displaying high IgE prevalences in the allergic population. There was an inverse relationship between allergenicity and amino acid conservation levels suggesting that allergenicity may be associated with the relative uniqueness of an antigen, i.e. immunogenicity, while sequence similarity leads to immunological tolerance. To assess how early in life parasite antigen sensitization occurs as this may have important effects on the development of allergy and on susceptibility to infectious, interferon-gamma and IL-4 responses in A. lumbricoides antigen-stimulated cord blood from newborns of infected and noninfected mothers by flow cytometry. There was evidence of higher frequencies of both IFN-gamma-expressing and IL-4-expressing CD4+ T cells (and IL-4 expressing basophils) in newborns of infected mothers than in newborns of noninfected mothers providing evidence of in utero sensitization helminth antigens and raising the possibility that the immunological effects of infection start in the fetus.